Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The iron responsive element binding protein (IRE-BP) regulates iron storage and uptake in response to iron. This control results from the interaction of the IRE-BP with the iron responsive element (IRE), a conserved sequence/structure element located near the 5' end of all ferritin mRNAs and in the 3' UTR of transferrin receptor mRNAs. Proteolysis was used to probe for functional elements of the IRE-BP. Partial chymotrypsin digestion generates a simple digestion pattern yielding fragments of 68, 56, 41, and 30 kDa. The 68 and 30 kDa fragments are derived from a single cleavage at Trp623. Further cleavages of the 68 kDa polypeptide yield the 56 and 41 kDa peptides. A combination of UV-crosslinking and chymotrypsin digestion was used to localize an RNA binding element within the C-terminus of the 68 kDa fragment, between amino acid residues 480 and 623. This region includes cysteine residues 503 and 506 which have been shown to be required for iron-sulfur cluster assembly and for iron regulation of the IRE-BP. Proteolytic fragments of the IRE-BP that contain this RNA binding region can be crosslinked to the IRE but do not bind with high affinity, suggesting that elements within the IRE-BP, in addition to those located between residues 480 and 623, are required for high affinity binding to the IRE.
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PMID:Localization of an RNA binding element of the iron responsive element binding protein within a proteolytic fragment containing iron coordination ligands. 751 18

The iron-responsive element-binding protein (IRE-BP) modulates both ferritin mRNA translation and transferrin receptor (TfR) mRNA stability by binding to specific mRNA sequences called iron-responsive elements (IREs). The regulation of IRE-BP in situ could possibly occur either through its Fe-S cluster and/or via free cysteine sulphydryl groups such as cysteine 437 (Philpott et al, J Biol Chem 268:17655, 1993; and Hirling et al, EMBO J 13:453, 1994). Recently, nitrogen monoxide (NO) has been shown to have markedly different biologic effects depending on its redox state (Lipton et al, Nature 364:626, 1993). Considering this fact, it is conceivable that the NO group, as either the nitrosonium ion (NO+) or nitric oxide (NO+), may regulate IRE-BP activity by S-nitrosylation of key sulphydryl groups or via ligation of NO. to the Fe-S cluster, respectively. This hypothesis has been examined using the NO+ generator, sodium nitroprusside (SNP); the NO. generator, S-nitroso-N-acetylpenicillamine (SNAP); and the NO./peroxynitrite (ONOO-) generator, 3-morpholinosydnonimine hydrochloride (SIN-1). Treatment of K562 cells for 18 hours with SNP (1 mmol/L) resulted in a pronounced decrease in both the RNA-binding activity of IRE-BP and the level of TfR mRNA. In addition, Scatchard analysis showed a marked decrease in the number of specific Tf-binding sites, from 590,000/cell (control) to 170,000/cell (test), and there was also a distinct decrease in Fe uptake. Furthermore, SNP did not decrease cellular viability or proliferation. In contrast, the NO. generator, SNAP (1 mmol/L), increased RNA-binding activity of IRE-BP, the level of TfR mRNA, and the number of TfRs in K562 cells. Moreover, both SNAP (1 mmol/L) and SIN-1 (0.5 mmol/L) reduced cellular proliferation. The results are discussed in context of the possible physiologic role of redox-related species of NO in regulating iron metabolism.
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PMID:The effect of redox-related species of nitrogen monoxide on transferrin and iron uptake and cellular proliferation of erythroleukemia (K562) cells. 757 17

Recombinant horse L-apoferritin and its mutants were used to compare the reactivities of two different cysteinyl residues with 7-fluoro-4-sulfamoyl-2,1,3-benzoxadiazole (ABD-F), p-chloromercuribenzoic acid (PCMB), N-(9-acridinyl)maleimide (NAM), and 4-maleimido-2,2,6,6-tetramethylpiperidine-N-oxyl (NEM-TEMPO). ABD-F selectively reacted with cysteine 52 (C52), which is located on the inner surface of the peptide shell of apoferritin. In contrast, PCMB reacted only with cysteine 130 (C130), which is located at the 3-fold channels of the shell. NAM and NEM-TEMPO reacted with both C52 and C130.
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PMID:Site-specific reactivities of cysteine residues in horse L-apoferritin. 760 10

This study was undertaken to characterize the nitric oxide complexes of mammalian ferritin and their EPR properties to gain a better understanding of the interaction of NO with non-heme iron proteins within the cell. Measurements were made with horse spleen apo- and holoferritins, with chemically modified proteins, and with recombinant human H-chain apoferritin and its site-directed mutants. Three types of EPR signals (A, B, and C) have been identified and attributed to iron-nitrosyl complexes at imidazole groups of histidine, thiol groups of cysteine, and carboxylate groups of aspartate and glutamate, respectively. The C-type axial spectrum has features at g perpendicular' = 4 and g parallel' = 2 characteristic of a paramagnetic Fe(3+)-NO- complex with total spin S = 3/2 and probably arises from nonspecific binding to carboxylate groups on the protein. The S = 1/2 axial B-type signal g perpendicular' = 2.033 and g parallel' = 2.014) is formed at Cys-130 (human H-chain sequence numbering). His-128 and possibly His-118 are sites of formation of the rhombic S = 1/2 A-type complex (gx' = 2.055, gy' = 2.033, and gz' = 2.015); the former residue perhaps plays a role in the conformational stability of the protein as well as in iron binding. The data reveal that the residues Cys-130 and His-128 in the vicinity of 3-fold channels leading to the interior of the protein shell are important in iron-nitrosyl complex formation in mammalian ferritins.
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PMID:Identification of the EPR-active iron-nitrosyl complexes in mammalian ferritins. 814 66

We previously demonstrated both mannose 6-phosphate receptor (MPR) and cathepsin L in early autophagic vacuoles of cultured rat fibroblasts. This suggested that the enzyme may originate either from the receptor-enriched prelysosomal compartment (PLC) or from the trans-Golgi network (TGN). In the present ultrastructural study, we elucidated the roles of the PLC and TGN in lysosomal enzyme delivery to autophagic vacuoles. Firstly, we studied whether endocytic markers, cationized ferritin (CF), bovine serum albumin-gold or horseradish peroxidase (HRP), can be detected in autophagic vacuoles. Autophagy was induced by serum removal from the medium with or without leupeptin, an inhibitor of cysteine proteinases. Endocytic markers were not detected in autophagic vacuoles after short uptake which filled the early endosome, but only after longer labeling which filled the PLC. The markers were usually found in advanced autophagic vacuoles containing partially degraded cytoplasm and complex internal membranes which are the characteristic of the PLC. HRP-positive vesicles were also observed in continuity with early autophagic vacuoles containing intact cytoplasm. After uptake and transport of CF and HRP to the PLC, these markers were delivered to autophagic vacuoles even if microtubules were disrupted in vinblastine before the induction of autophagy. Secondly, we studied whether MPRs transport cathepsin L to autophagic vacuoles directly from the TGN. Two inhibitors of MPR-mediated enzyme transport, tunicamycin and chloroquine, were used. Quantitative immunocytochemistry showed that neither of these drugs prevented cathepsin L delivery to autophagic vacuoles. The results suggest that a large proportion of lysosomal enzymes is delivered to autophagic vacuoles from the PLC by a microtubule-independent manner. The first enzymes may be transported in small PLC-derived vesicles or tubules which are reached by HRP but not by CF and gold. Later, the autophaged cytoplasm is delivered to larger vacuolar parts of the PLC. Mannose 6-phosphate receptors transport no or only trace amounts of lysosomal enzymes to autophagic vacuoles directly from the TGN.
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PMID:Autophagic vacuoles fuse with the prelysosomal compartment in cultured rat fibroblasts. 822 8

In an attempt to identify genes associated with Wallerian degeneration and peripheral nerve regeneration we have performed differential hybridization screening of a cDNA library from crushed rat sciatic nerve (7 days postlesion) using radioactively labeled cDNA prepared from poly(A)+ RNA of normal vs. crushed nerve. Screening of 5,000 randomly selected colonies yielded 24 distinct clones that were regulated following nerve injury. Fifteen of the differentially expressed sequences could be classified as induced, whereas 9 sequences appeared to be repressed at 1 week postcrush. Sequencing and computer-assisted sequence comparison revealed 3 classes of regulated cDNA clones representing 1) novel gene sequences (8 clones) including 3 transcripts containing a repetitive "brain identifier" (ID) element; 2) identified genes (7 clones) with previously undetected expression in the peripheral nervous system (PNS), such as apolipoprotein D, peripheral myelin protein 22kD (PMP22), SPARC (secreted protein, acidic and rich in cysteine), sulfated glycoprotein SGP-1, apoferritin, decorin, and X16/SRp20; and 3) identified genes (9 clones) with known expression in the PNS including, e.g., the myelin protein P0, gamma-actin, vimentin, alpha-tubulin, chargerin II, and cytochrome c-oxidase subunit I. Northern blot and polymerase chain reaction analyses with RNA from crushed and transected nerve demonstrated that sequences with related function, like the group of myelin genes, cytoskeleton genes, genes involved in RNA processing and translation, in lipid transport or energy metabolism showed closely related temporal patterns of expression during nerve degeneration and regeneration. Finally, we compared the differentially expressed genes identified at 7 days after crush injury (this investigation) with the regulated sequences isolated previously by De Leon et al. (J Neurosci Res 29:437-488, 1991) from a 3 day postcrush sciatic nerve cDNA library.
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PMID:Differentially expressed genes after peripheral nerve injury. 856 16

In plants, only ferritin gene expression has been reported to be iron-dependent. Here it is demonstrated that an iron overload of Brassica napus seedlings causes a large and rapid accumulation of ascorbate peroxidase transcripts, a plant-specific hydrogen peroxide-scavenging enzyme. This result documents a novel link between iron metabolism and oxidative stress. The ascorbate peroxidase mRNA abundance was not modified by reducing agents like N-acetyl cysteine, glutathione and ascorbate or by pro-oxidants such as hydrogen peroxide or diamide. Furthermore, the iron-induced ascorbate peroxidase mRNA accumulation was not antagonized by N-acetyl cysteine. Abscisic acid had no effect on the ascorbate peroxidase gene expression. Taken together these results suggest that iron-mediated expression of ascorbate peroxidase gene occurs through a signal transduction pathway apparently different from those already described for plant genes responsive to oxidative stress.
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PMID:Iron triggers a rapid induction of ascorbate peroxidase gene expression in Brassica napus. 923 28

H-kininogen is a multifunctional protein: it inhibits cysteine proteases, plays a role in contact activation of the coagulation cascade, and is the precursor of the potent proinflammatory peptide bradykinin. In the experiments described here, we identify H-kininogen as a ferritin-binding protein. Ferritin is a cellular and serum protein that is elevated in acute and chronic inflammation and many cancers. Despite numerous reports of ferritin-binding protein(s) in human serum, the nature and function of these proteins remain unclear. As a first step in characterizing the interaction between ferritin and its binding protein(s), we devised a ligand blot assay and used it to guide purification of a ferritin-binding protein from human serum. Edman degradation of the purified protein determined the sequence HNLGHGHK(H)ERDQGHG, a sequence with identity to residues 421-436 of human H-kininogen. These results were confirmed by demonstrating that commercially purified H-kininogen possessed ferritin binding activity and that ferritin binding could not be detected in plasma from kininogen-deficient individuals. Ligand blot assays mapped the ferritin binding domain to the light chain of H-kininogen chain, and revealed that both H and L recombinant ferritins possess H-kininogen binding activity. The unexpected identification of H-kininogen as a ferritin-binding protein may link ferritin in the complex chain of interactions by which H-kininogen mediates its multiple effects in contact activation and inflammation.
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PMID:Human H-kininogen is a ferritin-binding protein. 959 1

In insects, holoferritin is easily visible in the vacuolar system of tissues that filter the hemolymph and, at least in Lepidoptera, is abundant in the hemolymph. Sequences reported for insect secreted ferritins from Lepidoptera and Diptera have high sequence diversity. We examined the nature of this diversity for the first time by analyzing sequences of cDNAs encoding two ferritin subunits from one species, Calpodes ethlius (Lepidoptera, Hesperiidae). We found that insect secreted ferritin subunits are of two types with little resemblance to each other. Ferritin was isolated from iron loaded hemolymph of C. ethlius fifth instar larvae by differential centrifugation. The N-terminal amino acid sequences for the nonglycosylated subunit with Mr 24,000 (S) and the largest glycosylated subunit with Mr 31,000 (G) were determined. The N-termini of the two subunits were different and were used to construct degenerate PCR primers. The same cDNA products were amplified from cDNA libraries from the midgut which secretes holoferritin and from the fat body which secretes iron-poor apoferritin. The G subunit most closely resembles the glycosylated ferritin subunit from Manduca sexta and the S subunit resembles the Drosophila small subunit. The S and G subunits from Calpodes were dissimilar and distinct from the cytosolic ferritins of vertebrates and invertebrates. Additional sequences were obtained by 5' and 3' RACE from separate fat body and midgut RACE libraries. cDNAs encoding both subunits had a consensus iron responsive element (IRE) in a conserved cap-distal location of their 5' UTR. An integrin-binding RGD motif found in the G subunit and conserved in Manduca may facilitate iron uptake through a calreticulin (mobilferrin)/integrin pathway. Calpodes and other insect ferritins have conserved cysteine residues to which fatty acids can be linked. Dynamic acylation of ferritin may slow but not prevent its passage out of the ER.
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PMID:Secreted ferritin subunits are of two kinds in insects molecular cloning of cDNAs encoding two major subunits of secreted ferritin from Calpodes ethlius. 1056 Jan 39

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, resulting in an increased iron deposition and multiorgan failure. Recently a candidate gene of HH, termed HFE, has been identified on chromosome 6, coding for a protein homologous to major histocompatibility complex (MHC) class I molecules. Two mutations of the hemochromatosis gene leading to an exchange of cysteine to tyrosine at aminoacid 282 and histidine to asparagine at aminoacid 63, are retained responsible for the development of hereditary hemochromatosis. The Cys282Tyr-mutation disrupts a disulfid bond and thus abrogates binding of the mutant HFE-protein to beta 2-microglobulin and its presentation on the cell surface. The His63Asp-mutation seems to play a role in pH-regulated dissociation of the transferrin receptor/transferrin complex in the lysosome. Mutations of the HFE-protein alter the affinity of the transferrin receptor for its ligand transferrin and may thus cause an intracellular accumulation of iron. Knowledge of the responsible gene allows a molecular diagnosis of HH. The new genetic marker can be used for screening and confirmation of HH reducing the need for confirmatory liver biopsies. Compared to standard screening parameters like ferritin and transferrin saturation genetic testing will allow the diagnosis of HH in an early, asymptomatic state before iron accumulation has occurred. As a normal life expectancy of patients with HH can be achieved if iron reduction is initiated early, genetic testing may thus be of great benefit for patients with HH.
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PMID:[Hereditary hemochromatosis--new developments after discovery of the HFE gene]. 1066 43


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